Type 1 Diabetes is an organ-specific autoimmune disease characterized by hyperglycemia due to progressive loss of pancreatic beta cells. We have discovered that during T1D, pancreatic beta cells in mice and human acquire a fate reminiscent of senescence associated secretory phenotype (SASP). Senescent beta cells can remodel the islet environment in a paracrine manner by promoting bystander senescence and immune surveillance. We have developed drugs that selectively eliminated SASP beta cells without altering the abundance of the major immune cell types involved in the disease. Significantly, elimination of SASP beta cells halted progression of beta cell destruction and was sufficient to prevent diabetes (Thompson et al, 2019 Cell Metabolism in press). In this proposal, we address how DNA damage leads beta cells to acquire a senescent fate in a T1D setting and the role of DNA repair processes in inducing DNA damage. Such understanding will be important to establish how we can direct DNA repair pathways to eliminate or dampen the senescence of beta cells. We also investigate the transcriptional and chromatin changes in senescent beta cells and whether we can target key regulators to dampen the senescence phenotype. Finally, we explore whether extracellular vesicles from senescent beta cells are involved in cell-cell communication and transmitting signals to regulate the immune response. Such an approach will broaden upon our new finding on beta cell senescence in T1D and provide new direction to therapeutic development.